Skip to main content Skip to main navigation menu Skip to site footer

Potensi terapi kombinasi Liver Growth Factor (LGF) dan Adrenomedullin (ADM) sebagai harapan baru penatalaksanaan Azoospermia Non-Obstruktif (ANO): tinjauan pustaka



Abstract

Non-Obstructive Azoospermia (NOA) is caused by the failure of spermatogenesis process. This case becomes the highest prevalence, 95% of the total azoospermia. Therapeutic modalities in use today such as invasive techniques, hormonal therapy, and gene therapy are less effective in the treatment of azoospermia. In addition, the overall therapeutic modalities also have serious side effects such as infection, testicular atrophy, nerve damage and other side effects. Referring to the problems above, non-obstructive azoospermia is an urgent health issue and requires effective and efficient management with minimal side effects, as the combination of Liver Growth Factor (LGF) and Adrenomedullin (ADM). LGF is able to regenerate spermatogenesis after spermatogonia testicular stem cell damage. LGF also works specifically by stimulating germinal cells without changes in somatic cells. The motility of reactivation could be improved by combining the ADM into therapy, which bind to specific receptors, and the result of increasing the cAMP / PKA and NO that are important in the regulation of cilia’s movement. Combination LGF and ADM are potential to create new therapeutic candidates in the management of non-obstructive azoospermia, which can be immediately implemented as effective and efficient therapy.

 

Azoospermia Non-Obstruktif (ANO) adalah azoospermia yang disebabkan kegagalan proses spermatogenesis dan merupakan kasus dengan prevalensi tertinggi (95% dari total azoospermia). Modalitas terapi yang digunakan sampai saat ini seperti teknik invasif, terapi hormonal, dan terapi gen terbukti belum efektif dalam tatalaksana azoospermia. Selain itu, keseluruhan modalitas terapi ini juga memiliki efek samping serius yang perlu diwaspadai seperti infeksi, testis atropi, kerusakan saraf, serta efek samping lainnya. Merujuk pada permasalahan diatas, azoospermia non-obstruktif merupakan masalah kesehatan yang mendesak dan membutuhkan tatalaksana yang efektif dan efisien dengan efek samping yang minimal seperti dengan kombinasi terapi LGF dan ADM. LGF mampu meregenerasi testis dan mereaktivasi spermatogenesis setelah kerusakan sel punca spermatogonia. LGF juga bekerja secara spesifik dengan menstimulasi sel-sel germinal tanpa menyebabkan perubahan pada sel-sel somatis. Motilitas sperma hasil reaktivasi spermatogenesis kemudian ditingkatkan dengan mengkombinasikan ADM kedalam terapi dimana berikatan pada reseptor-reseptor spesifik sehingga berefek pada peningkatan cAMP/PKA dan NO yang penting dalam pengaturan kibasan flagella. Perpaduan antara terapi LGF dan ADM ini sangat berpotensi menciptakan kandidat terapi baru dalam penatalaksanaan NOA yang efektif dan efisien. 

Keywords: Adrenomedullin Azoospermia Non-Obstruktif Liver Growth Factor Motilitas Spermatogenesis

References

  1. World Health Organization. Health Topics: Infertility. WHO 2011 [cited 2011 Aug 25]. Available from: URL: HYPERLINK http://www.who.int/topics/infertility/en/.
  2. Human Reproduction Update. Male infertility and the involvement of the X chromosome. Hum Reprod Update. 2009;15(6):623-37.
  3. Fardilha M, Esteves SL, Gregório LK, Pelech S, da Cruz E Silva OA, et al. Protein phosphatase 1 complexes modulate sperm motility and present novel targets for male infertility. Hum Reprod. 2011;17(8):466-77.
  4. Cocuzza M, Sabanegh ES, Agarwal A. Varicocele – a dilema for the urologist current concepts. European genito-urinary disease. 2007.
  5. Male Infertility Best Practice Policy Committee of the American Urological Association; Practice Committee of the American Society for Reproductive Medicine. Report on evaluation of the azoospermic male. Fertil Steril. 2006;86(5 Suppl 1):S210-S215.
  6. Human Reproduction Update. Which is the best sperm retrieval technique for non-obstructive azoospermia? A systematic review. Hum Reprod Update. 2007;13(6):539-49.
  7. Mirilas P, Mentessidou A. Microsurgical subinguinal varicocelectomy in children, adolescents, and adults: surgical anatomy and anatomically justified technique. J Androl. 2012;33(3):338-349.
  8. Suryandari DA, Moeloek N, Citrawati M, Sari P, Yurnadi. Analisis mikrodelesi kromosom Y pada pria azoospermia di indonesia. Makara Kesehatan. 2006;10(1):41-6.
  9. Cayan S. Shavakhabov S, Kadio?lu A. Review: treatment of palpable varicocele in infertile men: a meta-analysis to define the best technique. J Androl 2009;30(1):33-40.
  10. Madhukar D, Rajender S. Hormonal treatment of male infertility: promises and pitfalls. J Androl . 2009;30:95-112.
  11. Lamb D. Would gene therapy for the treatment of male infertility be safe. Nat Clin Pract Urol. 2008;5:594-595.
  12. Diaz Gil JJ, Rua C, Machin C, Cereceda RM, García-Cañero R, de Foronda M, et al. Hepatic growth induced by injection of the liver growth factor into normal rats. Growth Regul 1994;4(3):113-22.
  13. D?´az-Gil JJ, Sa´nchez G, Trilla C, Escart?´n P. Identification of biliprotein as a liver growth factor. Hepatology. 1988;8:484–6.
  14. Lambrechts D, Storkebaum E, Morimoto M, Del-Favero J, Desmet F, Marklund SL, et al. VEGF is a modifier of amyotrophic lateral sclerosis in mice and humans and protects motorneurons against ischemic death. Nature Genetics 2003;34(4):383–94.
  15. Keith J, Kirk L, Anthony F, et al. CUA guideline: the workup of azoospermic males. Can Urol Assoc J 2010;4(3):163-7.
  16. Talas H, Yaman O, Aydos K. Outcome of repeated micro-surgical testicular sperm extraction in patients with non-obstructive azoospermia. Asian J Androl 2007;9(5): 668–73.
  17. Jarvi K, Lo K, Fischer A, Grantmyre J, Zini A, Chow V, et al. CUA Guideline: The workup of azoospermic males. Can Urol Assoc J 2010;4(3):163–7.
  18. D?´az-Gil JJ, Majano PL, Lo´pez-Cabrera M, Sánchez-López V, Rúa C, Machín C, et al. The mitogenic activity of the liver growth factor is mediated by tumor necrosis factor alpha in rat liver. J Hepatol. 2003;38(5):598–604.
  19. Robinson CJ, Stringer SE. The splice variants of vascular endothelial growth factor (VEGF) and their receptors. J Cell Sci. 2001;114:853-65.
  20. Li YY, Li L, Hwang IS, Tang F, O WS. Coexpression of adrenomedullin and its receptors in the reproductive system of the rat: effects on steroid secretion in rat ovary. Biol Reprod. 2008;79(2):200-208.
  21. Susan D, Andrew D. Vascular actions of calcitonin gene-related peptide and adrenomedullin. Physiol Rev. 2004;84(3):903–34.
  22. Terata K, Miura H, Liu Y, Loberiza F, Gutterman DD. Human coronary arteriolar dilation to adrenomedullin: role of nitric oxide and K+ channels. Am J Physiol Heart Circ Physiol. 2000;279(6):H2620-6.
  23. Chiu PC, Liao S, Lam KK, Tang F, Ho JC, Ho PC, et al. Adrenomedullin regulates sperm motility and oviductal ciliary beat via cyclic adenosine 5'-monophosphate/protein kinase A and nitric oxide. Endocrinology. 2010;151(7):3336-47.
  24. Hinson JP, Kapas S, Smith DM. Adrenomedullin, a multifunctional regulatory peptide. Endocr Rev. 2000;21(2):138–67.
  25. Prouty SM, Hanson KD, Boyle AL, Brown JR, Shichiri M, Follansbee MR, et al. A cell culture model system for genetic analyses of the cell cycle by targeted homologous recombination. Oncogene. 1993;8(4):899–907.
  26. Russell, David W, Sambrook. Molecular cloning: a laboratory manual. Cold Spring Harbor, N.Y: Cold Spring Harbor Laboratory. 2001.
  27. Hannig G, Makrides S. Strategies for optimizing heterologous protein expression in Escherichia coli. Trends in biotechnology 1998;16(2):54–60.
  28. Brondyk WH. Selecting an appropriate method for expressing a recombinant protein. Methods Enzymol. 2009;463:131–47.
  29. Martin-Hidalgo A, Lobo MVT, Sacristán S. Rat testicular regeneration after EDS administration is stimulated by the liver growth factor (LGF). FEBS J. 2007;274(F1-126):296.
  30. Hay DL, Howitt SG, Conner AC, Schindler M, Smith DM, Poyner DR l. CL/RAMP2 and CL/RAMP3 produce pharmacologically distinct adrenomedullin receptors: a comparison of effects of adrenomedullin 22–52, CGRP8–37 and BIBN4096BS. Br J Pharmacol 2003;140:477–86.
  31. Alves HNC, Silva ALM, Olsson IAS, Orden JMG, Antunes LM. Anestesia with intraperitoneal propofol, medetomidine, and fentanyl in rats. J Am Assoc Lab Anim Sci. 2010;49(4):454-9.
  32. Millar A, Hughes D, Kerr S. The safe preparation of injections in near-patient areas. Hospital Pharmacist. 2006;13:128–30.
  33. D?´az-Gil JJ, Gavilanes JG, Sa´nchez G, García-Cañero R, García-Segura JM, et al. Identification of a liver growth factor as an albumin–bilirubin complex. Biochem J. 1987;243(2):443–8.
  34. Diaz-Gil JJ, Munoz J, Albillos A, Rúa C, Machín C, García-Cañero R, et al. Improvement in liver fibrosis, functionality and hemodynamics in CCI4-cirrhotic rats after injection of the liver growth factor. J Hepatol. 1999;30(6):1065-72.
  35. Robinson CJ, Stringer SE. The splice variants of vascular endothelial growth factor (VEGF) and their receptors. J Cell Sci. 2001;114(Pt5):853-65.
  36. Martin-Hidalgo A, Arenas MI, Sacristán S. Rat testis localization of VEGFs and VEGF Receptors in control and testicular regeneration stimulated by the Liver growth factor (LGF). FEBS J. 2007;274(F1-125):296.
  37. Hicklin DJ, Ellis LM. Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. JCO. 2005;23(5):1011–27.
  38. Mac Gabhann F, Popel AS. Differential binding of VEGF isoforms to VEGF receptor 2 in the presence of neuropilin-1: a computational model. AJP Heart 2005;288(6):2851–60.
  39. Takahashi H, Shibuya M. The vascular endothelial growth factor (VEGF)/VEGF receptor system and its role under physiological and pathological conditions. Clinical Science. 2005;109(3):227–41.
  40. Matsumoto Y, Tanaka K, Hirata G, Hanada M, Matsuda S, Shuto T, et al. Possible involvement of the vascular endothelial growth factor-FLT1-focal adhesion kinase pathway in chemotaxis and the cell proliferation of osteoclast precursor cells in arthritic joints. J Immunol 2002;168(11):5824–31.
  41. Le Couter J, Moritz DR, Li B, Phillips GL, Liang XH, Gerber HP, et al. Angiogenesis-independent endothelial protection of liver: role of VEGFR-1. Science. 2003;299(5608):890–3.
  42. Tammela T, Enholm B, Alitalo K, Paavonen K. The biology of vascular endothelial growth factors. Cardiovascular Research. 2007;65(3):550–63.
  43. Bott RC, McFee RM, Clopton DT, Toombs C, Cupp AS. Vascular Endothelial Growth Factor and Kinase Domain Region Receptor Are Involved in Both Seminiferous Cord Formation and Vascular Development During Testis Morphogenesis in the Rat. Biol Reprod 2006;75(1):56–67.
  44. Takahashi T, Yamaguchi S, Chida K. and Shibuya M. A single autophosphorylation site on KDR/Flk-1 is essential for VEGF-A-dependent activation of PLC-? and DNA synthesis in vascular endothelial cells. EMBO J. 2000;20(11):2768–78.
  45. Sakurai Y, Ohgimoto K, Kataoka Y, Yoshida, N, Shibuya M. Essential role of Flk-1 (VEGF receptor 2) tyrosine residue 1173 in vasculogenesis in mice. Proc. Natl Acad. Sci. USA 2005;102(4):1076–81.
  46. Yamazaki Y, Morita T. Molecular and functional diversity of vascular endothelial growth factors. Molecular Diversity 2006;10(4):515–27.
  47. Gerber HP, McMurtrey A, Kowalski J, Yan M, Keyt BA, Dixit V, et al. Vascular endothelial growth factor regulates endothelial cell survival through the phosphatidylinositol 3_-kinase/ Akt signal transduction pathway. Requirement for Flk-1/KDR activation. J. Biol. Chem. 1998;273(46):30336–43.
  48. Fujio Y, Walsh K. Akt mediates cytoprotection of endothelial cells by vascular endothelial growth factor in an anchorage-dependent manner. J Biol Chem 1999;274(23):16349–54.
  49. Byzova TV, Goldman CK, Pampori N, Thomas KA, Bett A, Shattil SJ, et al. A mechanism for modulation of cellular responses to VEGF: activation of the integrins. Mol Cell. 2000;6(4):851–60.
  50. Ziman M, Preuss D, Mulholland J, O'Brien JM, Botstein D, Johnson DI. Subcellular localization of Cdc42p, a Saccharomyces cerevisiae GTP-binding protein involved in the control of cell polarity. Mol Biol Cell. 1993;4(12):1307-1316.
  51. Johnson DI, Pringle JR. Molecular characterization of CDC42, a saccharomyces cerevisiae gene involved in the development of cell polarity. J Cell Biol 1990;111(1):143-52.
  52. Ziman M, Preuss D, Mulholland J, O'Brien JM, Botstein D, Johnson DI. Subcellular localization of Cdc42p, a Saccharomyces cerevisiae GTP-binding protein involved in the control of cell polarity. Mol Biol Cell. 1993;4(12):1307-1316.
  53. Madden K, Snyder M. Cell polarity and morphogenesis in budding yeast. Annu Rev Microbiol. 1998;52:687-74.
  54. Adams AE, Johnson DI, Longnecker RM, Sloat BF, Pringle JR. CDC42 and CDC43, two additional genes involved in budding and the establishment of cell polarity in the yeast Saccharomyces cerevisiae. J Cell Biol. 1990;111(1):131-142.
  55. Lambrechts D, Storkebaum E, Morimoto M, Del-Favero J, Desmet F, Marklund SL, et al. VEGF is a modifier of amyotrophic lateral sclerosis in mice and humans and protects motorneurons against ischemic death. Nature Genetics. 2003;34(4):383–94.
  56. Jin K, Mao XO, Greenberg DA. Vascular endothelial growth factor stimulates neurite outgrowth from cerebral cortical neurons via rho kinase signaling. Journal of Neurobiology. 2006;66(3):236–42.
  57. Pérez-Crespo, Pericuesta E, Pérez-Cerezales S, Arenas MI, Lobo MV, Díaz-Gil JJ, et al. Effect of liver growth factor on both testicular regeneration and recovery of spermatogenesis in busulfan-treated mice. Reprod Biol Endocrinol 2011;9:21.
  58. Chiu PC, Liao S, Lam K, Tang F, Ho JC, Ho PC, et al. Adrenomedullin regulates sperm motility and oviductal ciliary beat via cyclic adenosine 5-monophosphate/protein kinase A and nitric oxide. Endocrinology. 2010;151(7):3336–47.
  59. Cosson J. A moving image of flagella: news and views on the mechanisms involved in axonemal beating. Cell Biol Int 1996;20(2):83–94.
  60. Stommel EW, Stephens RE. Cyclic AMP and calcium in the differential control of mytilus gill cilia. J Comp Physiol A 1985;157(4):451–9.
  61. Hamasaki T, Murtaugh TJ, Satir BH, Satir P. In vitro phosphorylation of paramecium axonemes and permeabilized cells. Cell Motil Cytoskeleton 1989;12(1):1-11.
  62. Christensen ST, Guerra C, Wada Y, Valentin T, Angeletti RH, Satir P, et al. A regulatory light chain of ciliary outer arm dynein in Tetrahymena thermophila. J Biol Chem. 2001;276(23):20048–54.
  63. Darszon A, Acevedo JJ, Galindo BE, Hernández-González EO, Nishigaki T, Treviño CL, et al. Sperm channel diversity and functional multiplicity. Reproduction. 2006;131(6):977–88.
  64. Publicover S, Harper CV, Barratt C. [Ca2+]i signalling in sperm-making the most of what you’ve got. Nat Cell Biol 2007;9(3):235–42.
  65. Salathe M, Bookman RJ. Mode of Ca2- action on ciliary beat frequency in single ovine airway epithelial cells. J Physiol. 1999;520(Pt 3):851–65.
  66. Zagoory O, Braiman A, Gheber L, Priel Z. Role of calcium and calmodulin in ciliary stimulation induced by acetylcholine. Am J Physiol Cell Physiol. 2001;280(1):C100–9.
  67. Yang P, Diener, Rosenbaum, Sale. Localization of calmodulin and dynein light chain LC8 in flagellar radial spokes. J Cell Biol. 2001;153(6):1315-25.
  68. Machado-Oliveira G, Lefie`vre L, Ford C, Herrero MB, Barratt C, Connolly TJ, et al. Mobilisation of Ca2- stores and flagellar regulation in human sperm by S-nitrosylation: a role for NO synthesised in the female reproductive tract. Development 2008;135(22):3677-86.
  69. Marinoni E, Di Iorio R, Villaccio B, Vellucci O, Di Netta T, Sessa M, et al. Adrenomedullin in human male reproductive system. Eur J Obstet Gynecol Reprod Biol. 2005;122(2):195–8.
  70. Brain SD, Grant AD. Vascular actions of calcitonin gene-related peptide and adrenomedullin. Physiol Rev. 2004;84(3):903–34.
  71. Nishida H, Sato T, Miyazaki M, Nakaya H. Infarct size limitation by adrenomedullin: protein kinase A but not PI3-kinase is linked to mitochondrial Kca channels. J Cardiores 2007;77(2):398-405.

How to Cite

Hartaningsih, N. M. D., Prabawa, I. P. Y., Putu, B. B. A. G., Sindhughosa, D. A., Manuaba, I. B. A. P., & Pramesemara, I. G. N. (2022). Potensi terapi kombinasi Liver Growth Factor (LGF) dan Adrenomedullin (ADM) sebagai harapan baru penatalaksanaan Azoospermia Non-Obstruktif (ANO): tinjauan pustaka. Intisari Sains Medis, 13(1), 202–209. https://doi.org/10.15562/ism.v13i1.1363
ACM ACS APA ABNT Chicago Harvard IEEE MLA Turabian Vancouver
Download Citation
Endnote/Zotero/Mendeley (RIS) BibTeX

HTML
38

Total
0

Share

Search Panel

Ni Made Dian Hartaningsih
Google Scholar
Pubmed
ISM Journal

I Putu Yuda Prabawa
Google Scholar
Pubmed
ISM Journal

Benediktus Bosman Ariesta Gusti Putu
Google Scholar
Pubmed
ISM Journal

Dwijo Anargha Sindhughosa
Google Scholar
Pubmed
ISM Journal

Ida Bagus Amertha Putra Manuaba
Google Scholar
Pubmed
ISM Journal

I Gusti Ngurah Pramesemara
Google Scholar
Pubmed
ISM Journal